ES2525535T3 - Process for the preparation of chiral 3-triazolyl sulfoxide derivatives - Google Patents

Abstract

Process for the preparation of 3-triazolyl-sulfoxide derivatives of general formula (I) in enantiomerically pure or enantiomerically enriched form. wherein X1 and X2 independently represent fluorine, chlorine, bromine, hydrogen, C1-C12 alkyl or C1-C12 haloalkyl, Y1 and Y2 independently represent fluorine, chlorine, bromine, hydrogen, C1-C12 alkyl or C1 haloalkyl - C12, R1 and R2 independently represent hydrogen, C1-C12 alkyl, C1-C12 halogenoalkyl, cyano, halogen or nitro, R3 represents hydrogen, C1-C12 alkyl, amino, nitro, NH (CO) -C1-C12 alkyl or N> = CR'R, in which R and R 'independently represent hydrogen, C1-C12 alkyl or aryl, characterized in that (A) a sulfide of formula (II) is reacted in which X1, X2, Y1, Y2, R1, R2 and R3 have the aforementioned meanings, in the presence of a chiral catalyst and an oxidizing agent, the oxidizing agent being selected from hydrogen peroxide, alkyl hydroperoxide and arylalkyl hydroperoxide and the chiral catalyst being a metal-chiral ligand complex and the metal a transition metal.

Description

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DESCRIPTION

Process for the preparation of chiral 3-triazolyl sulfoxide derivatives

The present invention relates to a catalytic process for the preparation of 3-triazolyl sulfoxide derivatives in enantiomerically pure or enantiomerically enriched form.

The chemical synthesis of 3-triazolyl sulfoxides is described in the literature, but leads to a racemic mixture (WO 1999/055668).

The enantiomerically pure chiral sulfoxides and the corresponding derivatives are of great importance in the pharmaceutical and agrochemical industry. Said compounds may be processed to procure exclusively the biologically active enantiomer of a chemical medicine or phytoprotective agent. This excludes not only residues from the preparation process, but also avoids the potentially harmful side effects that can be generated by the unwanted enantiomer. (Nugent et al., Science 1993, 259, 479; Noyori et al., CHEMTECH 1992, 22, 360).

The enantioselective synthesis of chiral sulfoxides is described in the literature. Summary articles are found describing this methodology, for example, in H. B. Kagan in "Catalytic Asymmetric Synthesis"; I. Ed. VCH: New York 1993, 203-226; Ojima N. Khiar in Chem. Rev. 2003, 103, 3651-3705; K. P. Bryliakov in Current Organic Chemistry 2008, 12, 386-404. In addition to the classical metal-catalyzed procedures for the synthesis of chiral sulfoxides, enzymatic and chromatographic procedures are also described in the literature (K. Kaber in "Biotransformations in Organic Synthesis", Springer Ed., 3rd ed. 1997; HL Holland, Nat Prod. Rep., 2001, 18, 171-181). In this regard, enzymatic processes are predominantly substrate specific and also the industrial realization is very expensive and expensive. For example, monooxygenases and peroxidases are important classes of enzymes that are capable of catalyzing a multiplicity of sulphides to sulfoxides (S. Colonna et al., Tetrahedron Asymmetry 1993, 4, 1981). However, it has been shown that the stereochemical result of enzymatic oxidation depends largely on the structure of the sulfide.

It is a procedure frequently used for the enantioselective oxidation of thioethers the well-known Kagan-modified Sharpless epoxidation procedure with chiral titanium complexes (J. Am. Chem. Soc. 1984, 106, 81888193). In this regard, the chiral titanium complex, composed of Ti (OPri) 4 and (+) - or (-) - diethyl tartrate (DET), is "deactivated" with an equivalent of water and the enantioselective oxidation of arylalkyl sulfide sulfide. However, good results were obtained with the Kagan reagent with a mixing ratio of Ti (OPri) 4 / DET / H2O =

1: 2: 1 and an organic peroxide (for example tert-butyl hydroperoxide). The good enantioselectivity of the described titanium complexes is accompanied by a low catalytic activity that is described by the necessary quantitative relationship between substrate and catalyst. Through this process, direct oxidation of simple arylalkyl sulfides such as, for example, arylmethyl sulfides, to optically active sulfoxides can be achieved. It has been found that asymmetric oxidation of, for example, functionalized alkyl sulfides under these conditions, is carried out with moderate enantioselectivity.

Pasini et al. they have certainly been able to oxidize phenylmethyl sulfide with low amounts of oxotitanium Schiff bases

(IV) chiral and hydrogen peroxide, but with bad enantiomeric excesses (ee values <20%) (Gaz. Chim. Ital. 1986, 116, 35-40). Colona et al. describe similar experiments with chiral titanium complexes of N-salicylic-Lamino acids (Org. Bioorg. Chem. 1987, 71-71). In addition, titanium-catalyzed procedures result in very expensive processing, which is very disadvantageous for an industrial-scale economic process.

An additional procedure is based on vanadium (IV) Schiff bases as effective catalysts for sulfide oxidation. The chiral catalyst is prepared in situ from VO (acac) 2 with a Schiff base of chiral amino alcohols (Synlett. 1998, 12, 1327-1328; Euro. J. Chem. 2009, 2607-2610). However, this process is limited to simple and non-fluorinated arylalkyl ethers such as, for example, p-tolylmethyl sulfide.

Until now, enantiomers of 3-triazolyl sulfoxides that are racemic according to methods known in the literature are obtained by costly separation by HPLC in chiral phases. The chromatographic separation of enantiomers in chiral stationary phases is not, however, generally suitable for large amounts of active ingredient, but only serves to procure smaller amounts. In addition, the use of HPLC in chiral phases is extremely expensive due to the high price of these materials and the high consumption of time, particularly on a preparatory scale.

There was therefore an urgent need for a catalytic procedure that was practicable particularly on an industrial scale. The invention is therefore based on the objective of providing said catalytic process which, in addition to the industrial feasibility, guarantees its economy, good yields and a variation of the enantiomeric relationship.

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those enantiomeric ratios in the given ranges that present an excess of (+) enantiomer.

Therefore, the enantiomeric excess can be found between 0% ee and 99% ee. The enantiomeric excess is an indirect measure of the enantiomeric purity of a compound and gives the proportion of a pure enantiomer in a mixture whose remaining part is the racemate of the compound.

5 If necessary, the enantiomeric excess can be considerably increased by subsequent crystallization with or without solvent. Such processes are known to the specialist and include particularly the preferred crystallization with an organic solvent or a mixture of organic solvents with water.

Preparation Examples:

Example 1: Synthesis of (+) - 1- {2,4-dimethyl-5 - [(2,2,2-trifluoroethyl) sulfinyl] phenyl} -3- (trifluoromethyl) -1H-1,2,4-triazole

10 10.3 g (27.54 mmol, 95%) of 1- {2,4-dimethyl-5 - [(2,2,2-trifluoroethyl) sulfanyl] phenyl} -3- were dissolved in a three-neck flask (trifluoromethyl) -1H-1,2,4-triazole and 145.8 mg (0.55 mmol) of vanadium acetylacetonate in 36 ml of chloroform and stirred for 10 minutes. Next, 275.8 mg (0.825 mmol) of (S) - (2,4-di-tert-butyl-6 - {(E) - {(1-hydroxy-3,3-dimethylbutan-2-yl) was added imino} methyl} phenol After 10 minutes, 5.66 g (50 mmol) of 30% H2O2 was dosed for 6 hours The reaction was monitored by HPLC After 4 hours of

After reaction, another 145.8 mg (0.55 mmol) of vanadium acetylacetonate and 275.8 mg of 2,4-di-tert-butyl-6 - {(E) [(1-hydroxy-3, 3-dimethylbutan-2-yl) imino] methyl} phenol in 4 ml of chloroform. Next, 40 ml of chloroform, 20 ml of water as well as 20 ml of thiosulfate solution were consecutively added. After separation of the aqueous phase, the organic phase was washed with water, dried over Na2SO4 and the solvent was evaporated in vacuo. 10.84 g of grayish brown crystals of (+) - 1- {2,4-dimethyl-5 - [(2,2,2-trifluoroethyl) sulfinyl] phenyl} -3- (trifluoromethyl) -1H-1 were obtained 2,4

20 triazole (98% yield, 93.1% HPLC purity) with a sulfone ratio of 2.81%. The enantiomeric excess was determined by chiral phase HPLC (Daicel Chiracel OJ-RH 150) with a ratio of 16.34: 83.66.

The enantiomeric ratio, for example by crystallization in CHCl3, was improved to 3.39: 96.61.

Table 1: Oxidation of 1- {2,4-dimethyl-5 - [(2,2,2-trifluoroethyl) sulfanyl] phenyl} -3- (trifluoromethyl) -1H-1, 2,4-triazole under different conditions:

Oxidation agent

Solvent Enantiomeric relationship

H2O2

CHCl3 16.34: 83.66

H2O2

CHCl3 3.39: 96.61 after crystallization from CHCl3

H2O2

CHCl3: toluene 18.54: 81.46

Tert-Butyl hydroperoxide

CHCl3 50.0: 50.0

Cumol hydroperoxide

CHCl3 50:50

H2O2

Acetonitrile 50:50

H2O2

DME 31.49: 68.51

H2O2

n-Butanol 36.61: 63.39

H2O2

Methanol 50:50

H2O2

Glacial acetic acid 42.58: 57.42

H2O2

AcOEt 35.18: 64.82

H2O2

THF 50:50

H2O2

Me-thf 36.0: 64.0

H2O2

4-Methoxybenzene 16.33: 83.67

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Claims (1)

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